The studies in this application are designed to investigate the role of PTEN, a phosphatase about which very little is known in the lung. Deleted in many human cancers, Pten was initially thought to be a cancer suppressor gene. Its stellar role however, has emerged only recently as a key regulator of Progenitor/Stem cell homeostasis in various tissues including the brain and the gut. Preliminary data in this application show that epithelial deletion of Pten using a novel Nkx2.1-cre leads to expansion of the cells within the bronchioalveolar duct junction BADJ, a known lung Progenitor/Stem cell niche. Based on this finding future studies will be based on the HYPOTHESIS that Pten regulates the pool of lung Progenitor/Stem cell population residing within the BADJ niche. Three Specific Aims will test the hypothesis. Specific Aim 1. To Characterize Functional Properties of Pten(d/d) Epithelial Cells. Specific Aim 2. To Determine the Role of AKT and -Catenin in the Ptend/d lung Phenotype Specific Aim 3. To Determine the Role of Pten in the Lung Mesenchyme: These Specific Aims represent a thorough and mechanistic analysis of the functional role of Pten in the lung and one of its disorders, pulmonary fibrosis. PUBLIC HEALTH RELEVANCE: This is a proposal to study a gene named Pten which controls the number of Progenitor/Stem cells in the lung. The studies address the specific role of Pten in a serious lung condition known as Pulmonary Fibrosis for which no treatment currently exists other than transplantation. The long-term goal of this project is to learn enough about Pten to be able to modify its function and therefore prevent or treat lung disease.